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Molecular Research of Alzheimer's Disease

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (15 February 2022) | Viewed by 35006

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Dr. Lorenzo Falsetti

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Department of Medical and Molecular Sciences, Università Politecnica delle Marche, 60126, Ancona, Italy
Interests: critical care medicine; internal medicine; clinical prediction; machine learning and big data analysis; atherosclerosis; Alzheimer's disease; atrial fibrillation; pulmonary embolism; ultrasounds in critical care
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Dear Colleagues,

Alzheimer’s Disease represents a growing health concern, since ageing demographics are actively contributing to a significant increase in its prevalence and incidence. The classical neuropathogenetic model, based on brain amyloid plaque deposition, neurofibrillary tangles and cholinergic system dysfunction is undergoing reconsideration and integration in light of the failure of both amyloid-targeted and cholinesterase-inhibiting therapies. A better understanding of the relationships between the classical pathogenetic pathways and newer hypotheses are urgently required to guide future research and develop effective drugs. The role of risk factors and comorbidities, such as vascular diseases and diabetes mellitus, as well as neurovascular unit dysfunction, are suggesting the existence of newer molecular mechanisms that could represent potential targets for effective Alzheimer’s Disease treatments. The aim of this Special Issue of Biomedicines is to provide an overview of the pathophysiologic role of newer and older molecular mechanisms of Alzheimer’s Disease and to advance new insights for the development of new therapeutic approaches. Moreover, it will focus on newer candidate markers of disease onset and progression. Both original articles and reviews will be considered for publication in this Special Issue.

Dr. Lorenzo Falsetti
Guest Editor

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Related Special Issue

Molecular Research of Alzheimer's Disease 2.0 in Biomedicines (2 articles)

Published Papers (12 papers)

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Editorial

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3 pages, 183 KiB

Open AccessEditorial

Molecular Research on Alzheimer’s Disease

by Lorenzo Falsetti

Biomedicines 2023, 11(7), 1883; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11071883 - 03 Jul 2023

Cited by 1 | Viewed by 696

Abstract

Alzheimer’s disease (AD) is the most common form of dementia worldwide [...] Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

Research

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14 pages, 1646 KiB

Open AccessArticle

Increased YKL-40 but Not C-Reactive Protein Levels in Patients with Alzheimer’s Disease

by Víctor Antonio Blanco-Palmero, Marcos Rubio-Fernández, Desireé Antequera, Alberto Villarejo-Galende, José Antonio Molina, Isidro Ferrer, Fernando Bartolome and Eva Carro

Biomedicines 2021, 9(9), 1094; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9091094 - 27 Aug 2021

Cited by 9 | Viewed by 2427

Abstract

Neuroinflammation is a common feature in Alzheimer’s (AD) and Parkinson’s (PD) disease. In the last few decades, a testable hypothesis was proposed that protein-unfolding events might occur due to neuroinflammatory cascades involving alterations in the crosstalk between glial cells and neurons. Here, we tried to clarify the pattern of two of the most promising biomarkers of neuroinflammation in cerebrospinal fluid (CSF) in AD and PD. This study included cognitively unimpaired elderly patients, patients with mild cognitive impairment, patients with AD dementia, and patients with PD. CSF samples were analyzed for YKL-40 and C-reactive protein (CRP). We found that CSF YKL-40 levels were significantly increased only in dementia stages of AD. Additionally, increased YKL-40 levels were found in the cerebral orbitofrontal cortex from AD patients in agreement with augmented astrogliosis. Our study confirms that these biomarkers of neuroinflammation are differently detected in CSF from AD and PD patients. Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

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14 pages, 2286 KiB

Open AccessArticle

Brain-Specific Gene Expression and Quantitative Traits Association Analysis for Mild Cognitive Impairment

by Shao-Xun Yuan, Hai-Tao Li, Yu Gu and Xiao Sun

Biomedicines 2021, 9(6), 658; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060658 - 08 Jun 2021

Cited by 2 | Viewed by 2195

Abstract

Transcriptome–wide association studies (TWAS) have identified several genes that are associated with qualitative traits. In this work, we performed TWAS using quantitative traits and predicted gene expressions in six brain subcortical structures in 286 mild cognitive impairment (MCI) samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. The six brain subcortical structures were in the limbic region, basal ganglia region, and cerebellum region. We identified 9, 15, and 6 genes that were stably correlated longitudinally with quantitative traits in these three regions, of which 3, 8, and 6 genes have not been reported in previous Alzheimer’s disease (AD) or MCI studies. These genes are potential drug targets for the treatment of early–stage AD. Single–Nucleotide Polymorphism (SNP) analysis results indicated that cis–expression Quantitative Trait Loci (cis–eQTL) SNPs with gene expression predictive abilities may affect the expression of their corresponding genes by specific binding to transcription factors or by modulating promoter and enhancer activities. Further, baseline structure volumes and cis–eQTL SNPs from correlated genes in each region were used to predict the conversion risk of MCI patients. Our results showed that limbic volumes and cis–eQTL SNPs of correlated genes in the limbic region have effective predictive abilities. Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

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16 pages, 6213 KiB

Open AccessArticle

The Insulin Receptor: A Potential Target of Amarogentin Isolated from Gentiana rigescens Franch That Induces Neurogenesis in PC12 Cells

by Lihong Cheng, Hiroyuki Osada, Tianyan Xing, Minoru Yoshida, Lan Xiang and Jianhua Qi

Biomedicines 2021, 9(5), 581; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050581 - 20 May 2021

Cited by 7 | Viewed by 2889

Abstract

Amarogentin (AMA) is a secoiridoid glycoside isolated from the traditional Chinese medicine, Gentiana rigescens Franch. AMA exhibits nerve growth factor (NGF)-mimicking and NGF-enhancing activities in PC12 cells and in primary cortical neuron cells. In this study, a possible mechanism was found showing the remarkable induction of phosphorylation of the insulin receptor (INSR) and protein kinase B (AKT). The potential target of AMA was predicted by using a small-interfering RNA (siRNA) and the cellular thermal shift assay (CETSA). The AMA-induced neurite outgrowth was reduced by the siRNA against the INSR and the results of the CETSA suggested that the INSR showed a significant thermal stability-shifted effect upon AMA treatment. Other neurotrophic signaling pathways in PC12 cells were investigated using specific inhibitors, Western blotting and PC12(rasN17) and PC12(mtGAP) mutants. The inhibitors of the glucocorticoid receptor (GR), phospholipase C (PLC) and protein kinase C (PKC), Ras, Raf and mitogen-activated protein kinase (MEK) significantly reduced the neurite outgrowth induced by AMA in PC12 cells. Furthermore, the phosphorylation reactions of GR, PLC, PKC and an extracellular signal-regulated kinase (ERK) were significantly increased after inducing AMA and markedly decreased after treatment with the corresponding inhibitors. Collectively, these results suggested that AMA-induced neuritogenic activity in PC12 cells potentially depended on targeting the INSR and activating the downstream Ras/Raf/ERK and PI3K/AKT signaling pathways. In addition, the GR/PLC/PKC signaling pathway was found to be involved in the neurogenesis effect of AMA. Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

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15 pages, 4425 KiB

Open AccessArticle

SIRT1-Dependent Upregulation of BDNF in Human Microglia Challenged with Aβ: An Early but Transient Response Rescued by Melatonin

by Grazia Ilaria Caruso, Simona Federica Spampinato, Giuseppe Costantino, Sara Merlo and Maria Angela Sortino

Biomedicines 2021, 9(5), 466; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050466 - 24 Apr 2021

Cited by 18 | Viewed by 3055

Abstract

Microglia represent a first-line defense in the brain. However, in pathological conditions such as Alzheimer’s disease (AD), a pro-inflammatory switch may occur, leading to loss of protective functions. Using the human microglial cell line HMC3, we showed that exposure to low concentrations of β-amyloid peptide 1-42 (Aβ42; 0.2 μM) initially (6 h) upregulated anti-inflammatory markers interleukin (IL)-4, IL-13, and brain-derived neurotrophic factor (BDNF). BDNF increase was prevented by selective inhibition of SIRT1 with EX527 (2 μM). Accordingly, these early effects were accompanied by a significant Aβ42-induced increase of SIRT1 expression, nuclear localization, and activity. SIRT1 modulation involved adenosine monophosphate-regulated kinase (AMPK), which was promptly (30 min) phosphorylated by Aβ42, while the AMPK inhibitor BML-275 (2 μM) attenuated Aβ42-induced SIRT1 increase. Initially observed microglial responses appeared transient, as microglial features changed when exposure to Aβ42 was prolonged (0.2 μM for 72 h). While SIRT1 and BDNF levels were reduced, the expression of inflammatory markers IL-1β and tumor necrosis factor (TNF)-α increased. This coincided with a rise in NF-kB nuclear localization. The effects of melatonin (1 μM) on prolonged microglial exposure to Aβ42 were analyzed for their protective potential. Melatonin was able to prolong SIRT1 and BDNF upregulation, as well as to prevent NF-kB nuclear translocation and acetylation. These effects were sensitive to the melatonin receptor antagonist, luzindole (25 μM). In conclusion, our data define an early microglial defensive response to Aβ42, featuring SIRT1-mediated BDNF upregulation that can be exogenously modulated by melatonin, thus identifying an important target for neuroprotection. Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

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Review

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16 pages, 1516 KiB

Open AccessReview

Shared Molecular Mechanisms among Alzheimer’s Disease, Neurovascular Unit Dysfunction and Vascular Risk Factors: A Narrative Review

by Lorenzo Falsetti, Giovanna Viticchi, Vincenzo Zaccone, Emanuele Guerrieri, Gianluca Moroncini, Simona Luzzi and Mauro Silvestrini

Biomedicines 2022, 10(2), 439; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020439 - 14 Feb 2022

Cited by 7 | Viewed by 3076

Abstract

Alzheimer’s disease (AD) is the most common type of dementia, affecting 24 million individuals. Clinical and epidemiological studies have found several links between vascular risk factors (VRF), neurovascular unit dysfunction (NVUd), blood-brain barrier breakdown (BBBb) and AD onset and progression in adulthood, suggesting a pathogenetic continuum between AD and vascular dementia. Shared pathways between AD, VRF, and NVUd/BBB have also been found at the molecular level, underlining the strength of this association. The present paper reviewed the literature describing commonly shared molecular pathways between adult-onset AD, VRF, and NVUd/BBBb. Current evidence suggests that VRF and NVUd/BBBb are involved in AD neurovascular and neurodegenerative pathology and share several molecular pathways. This is strongly supportive of the hypothesis that the presence of VRF can at least facilitate AD onset and progression through several mechanisms, including NVUd/BBBb. Moreover, vascular disease and several comorbidities may have a cumulative effect on VRF and worsen the clinical manifestations of AD. Early detection and correction of VRF and vascular disease by improving NVUd/BBBd could be a potential target to reduce the overall incidence and delay cognitive impairment in AD. Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

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22 pages, 2011 KiB

Open AccessReview

Potential Roles of Sestrin2 in Alzheimer’s Disease: Antioxidation, Autophagy Promotion, and Beyond

by Shang-Der Chen, Jenq-Lin Yang, Yi-Heng Hsieh, Tsu-Kung Lin, Yi-Chun Lin, A-Ching Chao and Ding-I Yang

Biomedicines 2021, 9(10), 1308; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101308 - 24 Sep 2021

Cited by 3 | Viewed by 2517

Abstract

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. It presents with progressive memory loss, worsens cognitive functions to the point of disability, and causes heavy socioeconomic burdens to patients, their families, and society as a whole. The underlying pathogenic mechanisms of AD are complex and may involve excitotoxicity, excessive generation of reactive oxygen species (ROS), aberrant cell cycle reentry, impaired mitochondrial function, and DNA damage. Up to now, there is no effective treatment available for AD, and it is therefore urgent to develop an effective therapeutic regimen for this devastating disease. Sestrin2, belonging to the sestrin family, can counteract oxidative stress, reduce activity of the mammalian/mechanistic target of rapamycin (mTOR), and improve cell survival. It may therefore play a crucial role in neurodegenerative diseases like AD. However, only limited studies of sestrin2 and AD have been conducted up to now. In this article, we discuss current experimental evidence to demonstrate the potential roles of sestrin2 in treating neurodegenerative diseases, focusing specifically on AD. Strategies for augmenting sestrin2 expression may strengthen neurons, adapting them to stressful conditions through counteracting oxidative stress, and may also adjust the autophagy process, these two effects together conferring neuronal resistance in cases of AD. Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

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19 pages, 1941 KiB

Open AccessReview

Systemic Actions of SGLT2 Inhibition on Chronic mTOR Activation as a Shared Pathogenic Mechanism between Alzheimer’s Disease and Diabetes

by Gabriela Dumitrita Stanciu, Razvan Nicolae Rusu, Veronica Bild, Leontina Elena Filipiuc, Bogdan-Ionel Tamba and Daniela Carmen Ababei

Biomedicines 2021, 9(5), 576; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050576 - 19 May 2021

Cited by 19 | Viewed by 3637

Abstract

Alzheimer’s disease (AD) affects tens of millions of people worldwide. Despite the advances in understanding the disease, there is an increased urgency for pharmacological approaches able of impacting its onset and progression. With a multifactorial nature, high incidence and prevalence in later years of life, there is growing evidence highlighting a relationship between metabolic dysfunction related to diabetes and subject’s susceptibility to develop AD. The link seems so solid that sometimes AD and type 3 diabetes are used interchangeably. A candidate for a shared pathogenic mechanism linking these conditions is chronically-activated mechanistic target of rapamycin (mTOR). Chronic activation of unrestrained mTOR could be responsible for sustaining metabolic dysfunction that causes the breakdown of the blood-brain barrier, tau hyperphosphorylation and senile plaques formation in AD. It has been suggested that inhibition of sodium glucose cotransporter 2 (SGLT2) mediated by constant glucose loss, may restore mTOR cycle via nutrient-driven, preventing or even decreasing the AD progression. Currently, there is an unmet need for further research insight into molecular mechanisms that drive the onset and AD advancement as well as an increase in efforts to expand the testing of potential therapeutic strategies aimed to counteract disease progression in order to structure effective therapies. Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

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28 pages, 2143 KiB

Open AccessReview

Critical Molecular and Cellular Contributors to Tau Pathology

by Liqing Song, Evan A. Wells and Anne Skaja Robinson

Biomedicines 2021, 9(2), 190; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020190 - 14 Feb 2021

Cited by 26 | Viewed by 4355

Abstract

Tauopathies represent a group of neurodegenerative diseases including Alzheimer’s disease (AD) that are characterized by the deposition of filamentous tau aggregates in the brain. The pathogenesis of tauopathies starts from the formation of toxic ‘tau seeds’ from hyperphosphorylated tau monomers. The presence of specific phosphorylation sites and heat shock protein 90 facilitates soluble tau protein aggregation. Transcellular propagation of pathogenic tau into synaptically connected neuronal cells or adjacent glial cells via receptor-mediated endocytosis facilitate disease spread through the brain. While neuroprotective effects of glial cells—including phagocytotic microglial and astroglial phenotypes—have been observed at the early stage of neurodegeneration, dysfunctional neuronal-glial cellular communication results in a series of further pathological consequences as the disease progresses, including abnormal axonal transport, synaptic degeneration, and neuronal loss, accompanied by a pro-inflammatory microenvironment. Additionally, the discovery of microtubule-associated protein tau (MAPT) gene mutations and the strongest genetic risk factor of tauopathies—an increase in the presence of the ε2 allele of apolipoprotein E (ApoE)—provide important clues to understanding tau pathology progression. In this review, we describe the crucial signaling pathways and diverse cellular contributors to the progression of tauopathies. A systematic understanding of disease pathogenesis provides novel insights into therapeutic targets within altered signaling pathways and is of great significance for discovering effective treatments for tauopathies. Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

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25 pages, 5131 KiB

Open AccessReview

Curcumin as Scaffold for Drug Discovery against Neurodegenerative Diseases

by Filippa Lo Cascio, Paola Marzullo, Rakez Kayed and Antonio Palumbo Piccionello

Biomedicines 2021, 9(2), 173; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020173 - 09 Feb 2021

Cited by 11 | Viewed by 4158

Abstract

Neurodegenerative diseases (NDs) are one of major public health problems and their impact is continuously growing. Curcumin has been proposed for the treatment of several of these pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the ability of this molecule to reduce inflammation and aggregation of involved proteins. Nevertheless, the poor metabolic stability and bioavailability of curcumin reduce the possibilities of its practical use. For these reasons, many curcumin derivatives were synthetized in order to overcome some limitations. In this review will be highlighted recent results on modification of curcumin scaffold in the search of new effective therapeutic agents against NDs, with particular emphasis on AD. Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

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Other

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8 pages, 272 KiB

Open AccessOpinion

Plasma Phospho-Tau-181 as a Diagnostic Aid in Alzheimer’s Disease

by Ioanna Tsantzali, Aikaterini Foska, Eleni Sideri, Evdokia Routsi, Effrosyni Tsomaka, Dimitrios K. Kitsos, Christina Zompola, Anastasios Bonakis, Sotirios Giannopoulos, Konstantinos I. Voumvourakis, Georgios Tsivgoulis and George P. Paraskevas

Biomedicines 2022, 10(8), 1879; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10081879 - 03 Aug 2022

Cited by 1 | Viewed by 1602

Abstract

Cerebrospinal fluid (CSF) biomarkers remain the gold standard for fluid-biomarker-based diagnosis of Alzheimer’s disease (AD) during life. Plasma biomarkers avoid lumbar puncture and allow repeated sampling. Changes of plasma phospho-tau-181 in AD are of comparable magnitude and seem to parallel the changes in CSF, may occur in preclinical or predementia stages of the disease, and may differentiate AD from other causes of dementia with adequate accuracy. Plasma phospho-tau-181 may offer a useful alternative to CSF phospho-tau determination, but work still has to be done concerning the optimal method of determination with the highest combination of sensitivity and specificity and cost-effect parameters. Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

14 pages, 1238 KiB

Open AccessCase Report

From Cerebrospinal Fluid Neurochemistry to Clinical Diagnosis of Alzheimer’s Disease in the Era of Anti-Amyloid Treatments. Report of Four Patients

by Ioanna Tsantzali, Fotini Boufidou, Eleni Sideri, Antonis Mavromatos, Myrto G. Papaioannou, Aikaterini Foska, Ioannis Tollos, Sotirios G. Paraskevas, Anastasios Bonakis, Konstantinos I. Voumvourakis, Georgios Tsivgoulis, Elisabeth Kapaki and George P. Paraskevas

Biomedicines 2021, 9(10), 1376; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101376 - 02 Oct 2021

Cited by 3 | Viewed by 2299

Abstract

Analysis of classical cerebrospinal fluid biomarkers, especially when incorporated in a classification/diagnostic system such as the AT(N), may offer a significant diagnostic tool allowing correct identification of Alzheimer’s disease during life. We describe four patients with more or less atypical or mixed clinical presentation, in which the classical cerebrospinal fluid biomarkers amyloid peptide with 42 and 40 amino acids (Aβ₄₂ and Aβ₄₀, respectively), phospho-tau (τ_P-181) and total tau (τ_Τ) were measured. Despite the unusual clinical presentation, the biomarker profile was compatible with Alzheimer’s disease in all four patients. The measurement of classical biomarkers in the cerebrospinal fluid may be a useful tool in identifying the biochemical fingerprints of Alzheimer’s disease, especially currently, due to the recent approval of the first disease-modifying treatment, allowing not only typical but also atypical cases to be enrolled in trials of such treatments. Full article

(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)

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